RNAi of cat-2, a Putative Tyrosine Hydroxylase, Increases Alpha Synuclein Aggregation and Associated Effects in Transgenic C. elegans

2012 ◽  
Vol 11 (4) ◽  
pp. 387-394 ◽  
Author(s):  
Supinder Kaur ◽  
Shreesh Raj Sammi ◽  
Pooja Jadiya ◽  
Aamir Nazir
Keyword(s):  
Tyrosine Hydroxylase ◽  
Alpha Synuclein ◽  
C Elegans ◽  
Alpha Synuclein Aggregation

Targeted Downregulation of Estradiol Binding Na+/H+ Exchanger Nhx-2, Mimics Calorie Restriction, Extends Reproductive Longevity and Ameliorates Effects Associated With Alpha Synuclein Aggregation In C. Elegans

2021 ◽  
Author(s):  
Shikha Shukla ◽  
Lalit Kumar ◽  
Arunabh Sarkar ◽  
Kottapalli Srivi ◽  
Aamir Nazir
Keyword(s):  
Reproductive Health ◽  
Neurodegenerative Diseases ◽  
Functional Characterization ◽  
Alpha Synuclein ◽  
Binding Potential ◽  
Estradiol Treatment ◽  
Reproductive Senescence ◽  
Knock Out ◽  
C Elegans ◽  
Alpha Synuclein Aggregation

Abstract Setting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to multiple disorders including neurodegenerative diseases, cardiovascular ailments and bone disorders amongst others. The present study, employing transgenic C. elegans that expresses ‘human’ alpha synuclein, endeavors to decipher the association of reproductive senescence with age-associated neurodegenerative diseases and behavioral ageing, under normal conditions and after being probed with estradiol. We carried out RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects. These studies led us to functional characterization of the Na+/H+ exchanger; nhx-2, expressed exclusively in gut. We found that RNAi of nhx-2 not only ameliorates the effects associated with alpha-Synuclein aggregation, but it also attunes effects related to behavioral aging including that of reproductive health-span and neuroprotection via mimicking dietary restriction, as it alters food absorption from the gut. We further elucidated that these effects are Sir-2.1 driven as nhx-2 knock out did not delay reproductive senescence in knock down condition of sir-2.1. To substantiate our findings, we performed whole transcriptome analysis in nhx-2 mutant strain. Our data revealed differential expression of 61 out of 62 hallmark genes of CR described by GenDR, in knock out condition of nhx-2. As estradiol plays a central role in both reproductive health as well as neuronal health, we subjected worms to exogenous estradiol treatment and observed that it led to elevated levels of nhx-2. Studies on structural binding analysis demonstrated significant binding potential of estradiol receptor NHR-14 with nhx-2 gene and ChIP analysis revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3). These studies identify nhx-2 as an important modulator that extends reproductive longevity and ameliorates effects associated with alpha synuclein aggregation in C elegans.

scholarly journals Studies on C. elegans probed with estradiol, elucidate the critical role of Na+/H+ exchanger, nhx-2 in reproductive senescence and neuronal health

2020 ◽  
Author(s):  
Shikha Shukla ◽  
Lalit Kumar ◽  
Arunabh Sarkar ◽  
Kottapalli Srividya ◽  
Aamir Nazir
Keyword(s):  
Dietary Restriction ◽  
Histone H3 ◽  
Alpha Synuclein ◽  
Lysine Methylation ◽  
Estradiol Treatment ◽  
Reproductive Senescence ◽  
C Elegans ◽  
Histone H3 Acetylation ◽  
Alpha Synuclein Aggregation ◽  
H3 Acetylation

AbstractSetting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to neurodegenerative diseases, cardiovascular and bone disorders amongst others. The present study deciphers the association of reproductive senescence, presence/absence of the sex hormone estradiol with age-associated neurodegenerative diseases. We employed RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects in the transgenic C. elegans. These studies led us to fuctional characterisation of the Na+/H+ exchanger, expressed exclusively in gut. We found that RNAi of nhx-2 ameliorates the affects associated with alpha-Synuclein aggregation via mimicking dietary restriction as it alters food absorption from the gut. Our studies further elucidated that such effects are Sir-2.1 driven as nhx-2 RNAi did not delay reproductive senescence when sir-2.1 was silenced concurrently. As estradiol plays a central role in both reproductive health as well as neuronal health, we performed structural binding analysis that demonstrated the binding potential of the estradiol receptor NHR-14 with nhx-2 gene. Hence, we treated the worms with estradiol and observed that the transcription levels of nhx-2 were elevated above the endogenous level. To unravel the underlying molecular mechanism of induction we performed ChIP analysis and it revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3).Graphical abstractHIGHLIGHTSSilencing of a sodium proton antiporter nhx-2 of gut ameliorates effects associated with alpha-Synuclein aggregation via mimicking dietary restriction in C. elegans.We have established a genetic cross to construct a strain that expresses mCherry SIR-2.1 ubiquitously and α-Synuclein in muscles, that assists in corroborating the link between NHX-2 and SIR-2.1.Human 17-β-Estradiol treatment induces the expression of nhx-2, through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3).Effects associated with nhx-2, including prolonged reproductive span and neuroprotective effects, are SIR-2.1 driven.nhx-2 silencing decreases alpha-Synuclein aggregation however estradiol mediated overexpression above the endogenus level, does not amend the aggregation any further.

Analysis of alpha-synuclein aggregation and associated pathologies in a cellular model of multiple system atrophy

2005 ◽  
Vol 32 (06) ◽  
Author(s):  
G Fillon ◽  
M Neumann ◽  
R Zufferey ◽  
P Aebischer ◽  
HA Kretzschmar ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Alpha Synuclein ◽  
Cellular Model ◽  
Alpha Synuclein Aggregation

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽  
2015 ◽  
Vol 5 (95) ◽  
pp. 77706-77715 ◽  
Author(s):  
Supinder Kaur ◽  
Aamir Nazir
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Caenorhabditis Elegans ◽  
Potential Role ◽  
Alpha Synuclein ◽  
C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

Are lysosomes potential therapeutic targets for Parkinson’s disease?

2021 ◽  
Vol 20 ◽  
Author(s):  
A. Petese ◽  
V. Cesaroni ◽  
S. Cerri ◽  
F. Blandini
Keyword(s):  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Genome Wide Association Studies ◽  
Lysosomal Dysfunction ◽  
Genome Wide ◽  
Nigrostriatal Neurons ◽  
Disease Modifying Treatment ◽  
Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy

2021 ◽  
pp. 1-11
Author(s):  
David I. Finkelstein ◽  
Jay J. Shukla ◽  
Robert A. Cherny ◽  
Jessica L. Billings ◽  
Eiman Saleh ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Pharmacokinetic Profile ◽  
Alpha Synuclein ◽  
Redox Activity ◽  
Substantia Nigra Pars Compacta ◽  
Drug Candidate ◽  
Older Volunteers ◽  
Control Food ◽  
Alpha Synuclein Aggregation

Background: An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson’s disease and shown that it is brain-penetrant, reduces iron accumulation and iron mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. Objective: To evaluate the efficacy of ATH434 in a mouse MSA model. Methods: The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. Results: ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric species of synuclein. Conclusion: ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA.

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